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PLoS Genetics

Marie C Matrka, Katherine A Cimperman, Sarah R Haas, Geraldine Guasch, Lisa A Ehrman, Ronald R Waclaw, Kakajan Komurov, Adam Lane, Kathryn A Wikenheiser-Brokamp, Susanne I Wells
Esophageal cancer occurs as either squamous cell carcinoma (ESCC) or adenocarcinoma. ESCCs comprise almost 90% of cases worldwide, and recur with a less than 15% five-year survival rate despite available treatments. The identification of new ESCC drivers and therapeutic targets is critical for improving outcomes. Here we report that expression of the human DEK oncogene is strongly upregulated in esophageal SCC based on data in the cancer genome atlas (TCGA). DEK is a chromatin-associated protein with important roles in several nuclear processes including gene transcription, epigenetics, and DNA repair...
March 14, 2018: PLoS Genetics
Sangyong Choi, Ya-Mei Hu, Mark E Corkins, Amy E Palmer, Amanda J Bird
Zinc is an essential trace element that is required for the function of a large number of proteins. As these zinc-binding proteins are found within the cytosol and organelles, all eukaryotes require mechanisms to ensure that zinc is delivered to organelles, even under conditions of zinc deficiency. Although many zinc transporters belonging to the Cation Diffusion Facilitator (CDF) families have well characterized roles in transporting zinc into the lumens of intracellular compartments, relatively little is known about the mechanisms that maintain organelle zinc homeostasis...
March 12, 2018: PLoS Genetics
Moran Brenner, Lior Lobel, Ilya Borovok, Nadejda Sigal, Anat A Herskovits
Listeria monocytogenes (Lm) is a saprophyte and intracellular pathogen. Transition to the pathogenic state relies on sensing of host-derived metabolites, yet it remains unclear how these are recognized and how they mediate virulence gene regulation. We previously found that low availability of isoleucine signals Lm to activate the virulent state. This response is dependent on CodY, a global regulator and isoleucine sensor. Isoleucine-bound CodY represses metabolic pathways including branched-chain amino acids (BCAA) biosynthesis, however under BCAA depletion, as occurs during infection, BCAA biosynthesis is upregulated and isoleucine-unbound CodY activates virulence genes...
March 12, 2018: PLoS Genetics
Steven Parker, Marcin G Fraczek, Jian Wu, Sara Shamsah, Alkisti Manousaki, Kobchai Dungrattanalert, Rogerio Alves de Almeida, Edith Invernizzi, Tim Burgis, Walid Omara, Sam Griffiths-Jones, Daniela Delneri, Raymond T O'Keefe
Noncoding RNAs (ncRNAs) are emerging as key regulators of cellular function. We have exploited the recently developed barcoded ncRNA gene deletion strain collections in the yeast Saccharomyces cerevisiae to investigate the numerous ncRNAs in yeast with no known function. The ncRNA deletion collection contains deletions of tRNAs, snoRNAs, snRNAs, stable unannotated transcripts (SUTs), cryptic unannotated transcripts (CUTs) and other annotated ncRNAs encompassing 532 different individual ncRNA deletions. We have profiled the fitness of the diploid heterozygous ncRNA deletion strain collection in six conditions using batch and continuous liquid culture, as well as the haploid ncRNA deletion strain collections arrayed individually onto solid rich media...
March 12, 2018: PLoS Genetics
Shruti Thapliyal, Amruta Vasudevan, Yongming Dong, Jihong Bai, Sandhya P Koushika, Kavita Babu
The C. elegans ortholog of mammalian calsyntenins, CASY-1, is an evolutionarily conserved type-I transmembrane protein that is highly enriched in the nervous system. Mammalian calsyntenins are strongly expressed at inhibitory synapses, but their role in synapse development and function is still elusive. Here, we report a crucial role for CASY-1 in regulating GABAergic synaptic transmission at the C. elegans neuromuscular junction (NMJ). The shorter isoforms of CASY-1; CASY-1B and CASY-1C, express and function in GABA motor neurons where they regulate GABA neurotransmission...
March 12, 2018: PLoS Genetics
Seyyedhassan Paylakhi, Cassandre Labelle-Dumais, Nicholas G Tolman, Michael A Sellarole, Yusef Seymens, Joseph Saunders, Hesham Lakosha, Wilhelmine N deVries, Andrew C Orr, Piotr Topilko, Simon Wm John, K Saidas Nair
A mismatch between optical power and ocular axial length results in refractive errors. Uncorrected refractive errors constitute the most common cause of vision loss and second leading cause of blindness worldwide. Although the retina is known to play a critical role in regulating ocular growth and refractive development, the precise factors and mechanisms involved are poorly defined. We have previously identified a role for the secreted serine protease PRSS56 in ocular size determination and PRSS56 variants have been implicated in the etiology of both hyperopia and myopia, highlighting its importance in refractive development...
March 12, 2018: PLoS Genetics
Ezequiel Nazer, Ryan K Dale, Madoka Chinen, Behram Radmanesh, Elissa P Lei
Drosophila Argonaute2 (AGO2) has been shown to regulate expression of certain loci in an RNA interference (RNAi)-independent manner, but its genome-wide function on chromatin remains unknown. Here, we identified the nuclear scaffolding protein LaminB as a novel interactor of AGO2. When either AGO2 or LaminB are depleted in Kc cells, similar transcription changes are observed genome-wide. In particular, changes in expression occur mainly in active or potentially active chromatin, both inside and outside LaminB-associated domains (LADs)...
March 12, 2018: PLoS Genetics
Damla Tas, Luca Stickley, Federico Miozzo, Rafael Koch, Nicolas Loncle, Virginie Sabado, Bettina Gnägi, Emi Nagoshi
Forkhead box (FOXO) proteins are evolutionarily conserved, stress-responsive transcription factors (TFs) that can promote or counteract cell death. Mutations in FOXO genes are implicated in numerous pathologies, including age-dependent neurodegenerative disorders, such as Parkinson's disease (PD). However, the complex regulation and downstream mechanisms of FOXOs present a challenge in understanding their roles in the pathogenesis of PD. Here, we investigate the involvement of FOXO in the death of dopaminergic (DA) neurons, the key pathological feature of PD, in Drosophila...
March 12, 2018: PLoS Genetics
Anurag Kumar Sinha, Christophe Possoz, Adeline Durand, Jean-Michel Desfontaines, François-Xavier Barre, David R F Leach, Bénédicte Michel
It was recently reported that the recBC mutants of Escherichia coli, deficient for DNA double-strand break (DSB) repair, have a decreased copy number of their terminus region. We previously showed that this deficit resulted from DNA loss after post-replicative breakage of one of the two sister-chromosome termini at cell division. A viable cell and a dead cell devoid of terminus region were thus produced and, intriguingly, the reaction was transmitted to the following generations. Using genome marker frequency profiling and observation by microscopy of specific DNA loci within the terminus, we reveal here the origin of this phenomenon...
March 9, 2018: PLoS Genetics
Megan M Senchuk, Dylan J Dues, Claire E Schaar, Benjamin K Johnson, Zachary B Madaj, Megan J Bowman, Mary E Winn, Jeremy M Van Raamsdonk
Mild deficits in mitochondrial function have been shown to increase lifespan in multiple species including worms, flies and mice. Here, we study three C. elegans mitochondrial mutants (clk-1, isp-1 and nuo-6) to identify overlapping genetic pathways that contribute to their longevity. We find that genes regulated by the FOXO transcription factor DAF-16 are upregulated in all three strains, and that the transcriptional changes present in these worms overlap significantly with the long-lived insulin-IGF1 signaling pathway mutant daf-2...
March 9, 2018: PLoS Genetics
Ulrika A Hänninen, Riku Katainen, Tomas Tanskanen, Roosa-Maria Plaketti, Riku Laine, Jiri Hamberg, Ari Ristimäki, Eero Pukkala, Minna Taipale, Jukka-Pekka Mecklin, Linda M Forsström, Esa Pitkänen, Kimmo Palin, Niko Välimäki, Netta Mäkinen, Lauri A Aaltonen
Small bowel adenocarcinoma (SBA) is an aggressive disease with limited treatment options. Despite previous studies, its molecular genetic background has remained somewhat elusive. To comprehensively characterize the mutational landscape of this tumor type, and to identify possible targets of treatment, we conducted the first large exome sequencing study on a population-based set of SBA samples from all three small bowel segments. Archival tissue from 106 primary tumors with appropriate clinical information were available for exome sequencing from a patient series consisting of a majority of confirmed SBA cases diagnosed in Finland between the years 2003-2011...
March 9, 2018: PLoS Genetics
Jennifer C Hocking, Jakub K Famulski, Kevin H Yoon, Sonya A Widen, Cassidy S Bernstein, Sophie Koch, Omri Weiss, Seema Agarwala, Adi Inbal, Ordan J Lehmann, Andrew J Waskiewicz
The eye primordium arises as a lateral outgrowth of the forebrain, with a transient fissure on the inferior side of the optic cup providing an entry point for developing blood vessels. Incomplete closure of the inferior ocular fissure results in coloboma, a disease characterized by gaps in the inferior eye and recognized as a significant cause of pediatric blindness. Here, we identify eight patients with defects in tissues of the superior eye, a congenital disorder that we term superior coloboma. The embryonic origin of superior coloboma could not be explained by conventional models of eye development, leading us to reanalyze morphogenesis of the dorsal eye...
March 9, 2018: PLoS Genetics
Zhenfei Sun, Min Li, Ying Zhou, Tongtong Guo, Yin Liu, Hui Zhang, Yuda Fang
Light and microRNAs (miRNAs) are key external and internal signals for plant development, respectively. However, the relationship between the light signaling and miRNA biogenesis pathways remains unknown. Here we found that miRNA processer proteins DCL1 and HYL1 interact with a basic helix-loop-helix (bHLH) transcription factor, phytochrome-interacting factor 4 (PIF4), which mediates the destabilization of DCL1 during dark-to-red-light transition. PIF4 acts as a transcription factor for some miRNA genes and is necessary for the proper accumulation of miRNAs...
March 9, 2018: PLoS Genetics
Christian Beck, Henning Knoop, Ralf Steuer
Cyanobacteria are a monophyletic phylogenetic group of global importance and have received considerable attention as potential host organisms for the renewable synthesis of chemical bulk products from atmospheric CO2. The cyanobacterial phylum exhibits enormous metabolic diversity with respect to morphology, lifestyle and habitat. As yet, however, research has mostly focused on few model strains and cyanobacterial diversity is insufficiently understood. In this respect, the increasing availability of fully sequenced bacterial genomes opens new and unprecedented opportunities to investigate the genetic inventory of organisms in the context of their pan-genome...
March 9, 2018: PLoS Genetics
Ling Cao, Sheng Wang, Prakash Venglat, Lihua Zhao, Yan Cheng, Shengjian Ye, Yuan Qin, Raju Datla, Yongming Zhou, Hong Wang
In most plants, the female germline starts with the differentiation of one megaspore mother cell (MMC) in each ovule that produces four megaspores through meiosis, one of which survives to become the functional megaspore (FM). The FM further develops into an embryo sac. Little is known regarding the control of MMC formation to one per ovule and the selective survival of the FM. The ICK/KRPs (interactor/inhibitor of cyclin-dependent kinase (CDK)/Kip-related proteins) are plant CDK inhibitors and cell cycle regulators...
March 7, 2018: PLoS Genetics
Christy L Rhine, Kamil J Cygan, Rachel Soemedi, Samantha Maguire, Michael F Murray, Sean F Monaghan, William G Fairbrother
Substitutions that disrupt pre-mRNA splicing are a common cause of genetic disease. On average, 13.4% of all hereditary disease alleles are classified as splicing mutations mapping to the canonical 5' and 3' splice sites. However, splicing mutations present in exons and deeper intronic positions are vastly underreported. A recent re-analysis of coding mutations in exon 10 of the Lynch Syndrome gene, MLH1, revealed an extremely high rate (77%) of mutations that lead to defective splicing. This finding is confirmed by extending the sampling to five other exons in the MLH1 gene...
March 5, 2018: PLoS Genetics
Jason Liang, Bin-Zhong Li, Alexander P Tan, Richard D Kolodner, Christopher D Putnam, Huilin Zhou
Mms21, a subunit of the Smc5/6 complex, possesses an E3 ligase activity for the Small Ubiquitin-like MOdifier (SUMO). Here we show that the mms21-CH mutation, which inactivates Mms21 ligase activity, causes increased accumulation of gross chromosomal rearrangements (GCRs) selected in the dGCR assay. These dGCRs are formed by non-allelic homologous recombination between divergent DNA sequences mediated by Rad52-, Rrm3- and Pol32-dependent break-induced replication. Combining mms21-CH with sgs1Δ caused a synergistic increase in GCRs rates, indicating the distinct roles of Mms21 and Sgs1 in suppressing GCRs...
March 5, 2018: PLoS Genetics
Franziska S Kemter, Sonja J Messerschmidt, Nadine Schallopp, Patrick Sobetzko, Elke Lang, Boyke Bunk, Cathrin Spröer, Jennifer K Teschler, Fitnat H Yildiz, Jörg Overmann, Torsten Waldminghaus
Vibrio cholerae, the causative agent of the cholera disease, is commonly used as a model organism for the study of bacteria with multipartite genomes. Its two chromosomes of different sizes initiate their DNA replication at distinct time points in the cell cycle and terminate in synchrony. In this study, the time-delayed start of Chr2 was verified in a synchronized cell population. This replication pattern suggests two possible regulation mechanisms for other Vibrio species with different sized secondary chromosomes: Either all Chr2 start DNA replication with a fixed delay after Chr1 initiation, or the timepoint at which Chr2 initiates varies such that termination of chromosomal replication occurs in synchrony...
March 5, 2018: PLoS Genetics
Colin D Donohoe, Gábor Csordás, Andreia Correia, Marek Jindra, Corinna Klein, Bianca Habermann, Mirka Uhlirova
Interplay between apicobasal cell polarity modules and the cytoskeleton is critical for differentiation and integrity of epithelia. However, this coordination is poorly understood at the level of gene regulation by transcription factors. Here, we establish the Drosophila activating transcription factor 3 (atf3) as a cell polarity response gene acting downstream of the membrane-associated Scribble polarity complex. Loss of the tumor suppressors Scribble or Dlg1 induces atf3 expression via aPKC but independent of Jun-N-terminal kinase (JNK) signaling...
March 1, 2018: PLoS Genetics
Megan Roytman, Gleb Kichaev, Alexander Gusev, Bogdan Pasaniuc
Recent studies have identified thousands of regions in the genome associated with chromatin modifications, which may in turn be affecting gene expression. Existing works have used heuristic methods to investigate the relationships between genome, epigenome, and gene expression, but, to our knowledge, none have explicitly modeled the chain of causality whereby genetic variants impact chromatin, which impacts gene expression. In this work we introduce a new hierarchical fine-mapping framework that integrates information across all three levels of data to better identify the causal variant and chromatin mark that are concordantly influencing gene expression...
February 26, 2018: PLoS Genetics
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